Carbamazepine, or 5-carbamoyl-5H-dibenz(b,f)azepine (or 5H-dibenz(b,f)azepine-5-carboxamide or N-carbamoyliminostilbene), is an iminostilbene derivative which is a known analgesic and anticonvulsant used for the treatment of epilepsy, the pain associated with trigeminal neuralgia, psychomotor and grand mal seizures, and neurological disorders such as chronic pain states and headaches. Additionally, carbamazepine is used in various psychiatric disorders such as bipolar disorder, depression, cocaine addiction, alcohol addiction, opiate addiction, nicotine addiction, other obsessive compulsive disorders and cardiovascular disease. 
Carbamazepine and its synthesis are described in U.S. Pat. No. 2,948,718. Other processes for synthesizing carbamazepine are described in EP 0 029 409, EP 0 277 095, EP 0 688 768, EP 0 423 679, and EP 0 485 685.
Carbamazepine extended-release formulations have been developed in recent years to decrease daily fluctuations in serum carbamazepine concentration by smoothing out bloods levels of the drug and to improve dosing convenience. These extended-release formulations are typically designed to provide carbamazepine at a therapeutic range of from about 4 μg/ml to about 12 μg/ml of carbamazepine over a period of time. Blood levels of carbamazepine of less than 4 μg/ml have been found to be ineffective in treating clinical disorders while blood levels greater than 12 μg/ml have been found to be likely to result in undesirable side effects such as neuromuscular disturbances, cardiovascular and gastrointestinal effects.
SPD417 and Carbatrol® (both from Shire US Inc., Newport, Ky.) are extended-release preparations of carbamazepine which has allowed for twice daily administration of the drug in patients (See U.S. Pat. No. 5,326,570 and U.S. Pat. No. 5,912,013 which describe the formulation of carbamazepine). Currently, Carbatrol® is approved by the FDA for use in the treatment of epilepsy and pain associated with trigeminal neuralgia. For treating epilepsy, the usual initial dose for adults and children over 12 years of age is 200 mg taken twice daily. The dosage is then increased at weekly intervals by adding 200 mg/day. The dosage should generally not exceed 1,000 mg daily in children 12 to 15 years old and 1,200 mg daily for adults and children over 15 (dosages up to 1600 mg daily have been used for adults. For maintenance, the daily dosage is generally 800 to 1,200 mg. For treating trigeminal neuralgia, the usual dose is 200 mg on the first day and may be increased by up 200 mg every 12 hours as needed to achieve freedom from pain. The doses should not exceed 1,200 mg daily and the maintenance dose is usually in the range of 400 mg to 800 mg.
Tegretrol-XR® is another extended release, oral formulation of carbamazepine (sold by Novartis Pharmaceuticals) which is approved by the FDA for the treatment of epilepsy and the pain associated with trigeminal neuralgia. The suggested dosage regimens for Tegretrol-XR® are the same as for the Carbatrol® extended release formulation.
The range of therapeutic options for bipolar disorder has included in recent years several anticonvulsants and antipsychotic medications. Carbamazepine, a major antiepileptic drug used in treating convulsive, simple and complex partial seizures, has also long been considered one of the standard therapies for bipolar disorder, although it is not approved for this use by the FDA (drugs currently approved by FDA for the treatment of acute mania include lithium, valproate, chlorpromazine, olanzapine and lamotrigine). See, e.g., Okuma et al., “Anti-Manic and Prophylactic Effects of Carbamazepine (Tegretol®) on Manic Depressive Psychosis,” Folia Psychiatrica et Neurologica Japonica, 27:4, pp. 283–297 (1973); Okuma et al., “Comparison of the Antimanic Efficacy of Carbamazepine and Chlorpromazine in Mania: A Double-Blind Trial,” Psychopharmacology, 66, pp. 211–217 (1979); Grossi et al., “Carbamazepine vs Chlorpromazine: A Double-Blind Controlled Study,” in: Emrich et al. (eds) Anticonvulsants in Affective Disorders, Princeton, N.J., Excerpta Medica, pp. 177–187 (1984); Lerer et al, “Carbamazepine Versus Lithium in Mania: A Double-Blind Study,” J. Clin. Psychiatry, 48:3, pp. 89–93 (1987); Okuma et al., “Comparison of the Antimanic Efficacy of Carbamazepine and Lithium Carbonate by Double-Blind Controlled Study,” Pharmacopsychiatry, 23, pp. 143–150 (1990); and Keck et al., “Carbamazepine and Valporate in the Maintenance Treatment of Bipolar Disorder,” J. Clin. Psychiatry, 63 (Suppl 10), pp. 13–17 (2002).
However, in the treatment of bipolar disorder, carbamazepine has been used mainly in immediate-release preparations which need to be administered three or four times daily to avoid potentially problematic serum drug fluctuations. Also, in these treatments, carbamazepine has generally been administered at a constant dosage (see, e.g., Okuma et al. (1973)), at an initial constant dosage with subsequent adjustment (see, Okuma et al. (1979)), or at a gradually increasing dosage (See, e.g., Lerer et al. (1987)).
As described above, the generally accepted method for administering extended-release carbamazepine in the treatment of epilepsy has been to initiate a patient with 200 mg/day twice daily of carbamazepine with weekly increases of up to 200 mg/day until the optimal response was obtained. This dosage regime has also been used for the treatment of bipolar disease. Despite the treatments which are presently available with carbamazepine, there is a need to treat bipolar disorder using a more rapid treatment period than that which has been previously used.
Goldberg et al. [J. Clin. Psychiatry, 59:4, pp. 151–158, April 1998] reports the results of a retrospective study comparing the time to remission for pure and mixed manic bipolar patients who were treated with lithium, carbamazepine, divalproex, or combinations thereof. Of the 120 subjects included in this study, only 7 subjects took carbamazepine alone (4 mixed manic; 3 pure manic). Goldberg et al. conclude that the time course to remission “appears to be strongly influenced by the speed which patients achieve a therapeutic serum level of an antimanic agent.” In the study, the minimum therapeutic serum level for carbamazepine was ≧8 μg/mL. Goldberg et al. do not describe the dosage regimens used in the study for administering carbamazepine.
Vasudev et al. [Psychopharmacology, 150:15–23 (2000)] report the results of a study comparing carbamazepine and valproate monotherapies. In the study, carbamazepine was given orally in the form of 200 mg tablets. The subjects treated with carbamazepine were initially given 400 mg/day in two divided doses. The dose was then increased by 200 mg/day or 400 mg/day for the next two days. Thereafter, the dose was increased 200–400 mg at weekly intervals. This was continued until clinical improvement occurred, or a serum level not exceeding 14 μg/ml was reached, or dose limiting adverse effects occurred. The therapeutic serum level window used in the study for carbamazepine was 6–12 μg/ml. In the study, favorable clinical responses were considered responses that showed a more than 50% fall in YMRS scores from baseline. Vasudev et al. conclude from the results of the study that both carbamazepine and valproate monotherapies are feasible but the valproate monotherapy is more efficacious.
Bipolar disorder is a brain disorder which causes unusual shifts in a person's mood, energy and ability to function. The symptoms of bipolar are quite severe and can even result in suicide. Therefore, there remains a need for methods of treating bipolar disorder with carbamazepine that provide efficacy while minimizing the time it takes for the patient to reach efficacy and thus providing an effective method of treating bipolar disorder.